Introduction
Sepsis-associated acute kidney injury (S-AKI) is common among critically ill patients [
1‐
4]. S-AKI is associated with an increased risk of Intensive Care Unit (ICU) or hospital mortality [
5,
6]. Further, the individual syndromes of sepsis and AKI each render a patient more vulnerable to the other [
7]. Available evidence does not suggest that standard renal replacement therapies improve outcomes beyond control of fluid balance and azotemia [
8]. Thus, novel approaches are necessary to prevent and treat S-AKI.
Sepsis and S-AKI result from a dysregulated immune response [
9]. Foreign antigens bind to innate immune receptors and subsequently activate inflammasome components, ultimately leading to the elevated release of proinflammatory cytokines both systemically and locally [
9]. The resultant cytokine storm is associated with increased levels of Interleukin-6 (IL-6) [
10]. Multiple reports indicate that IL-6 is an excellent biomarker of severity and a prognostic indicator in patients with sepsis [
11‐
15]. Findings pertaining to the therapeutic utility of IL-6 inhibition in S-AKI remain mixed [
16,
17], suggesting that processes upstream of IL-6 may be responsible for triggering the deleterious effects in sepsis and S-AKI.
Galectin-3 (Gal-3) is a pleiotropic glycan-binding protein involved in numerous physiological and pathological events [
18], including those that relate to immune function [
19]. Epidemiologic studies have found an association between serum Gal-3 level and risk of sepsis [
20‐
22] as well as development of chronic kidney disease (CKD) [
23‐
25]. Pertinent findings show that serum Gal-3 predicts 30-day all-cause mortality in sepsis [
26], preoperative serum Gal-3 predicts AKI after cardiac surgery [
27], and serum Gal-3 at ICU discharge is associated with severity of AKI [
28]. However, no previous study has examined the relationship between serum Gal-3 at the time of admission and the subsequent development of AKI in patients with sepsis. Additionally, the temporal relationship between Gal-3 and IL-6 in the pathophysiology of S-AKI has never before been explored.
Prior murine studies have demonstrated the importance of Gal-3 in the pathogenesis of sepsis [
29,
30] and kidney disease [
31,
32], including AKI [
28,
33‐
36]. Pharmacologic inhibition of Gal-3 has ameliorated nephropathy induced by renal ischemia–reperfusion (IR) [
28], unilateral ureteral obstruction [
29], folic acid [
34], hypertension [
37,
38], aldosterone [
39], unilateral nephrectomy [
40], obesity [
41], aortic stenosis [
41], and cisplatin [
42]. However, no murine experiment has evaluated the relationship between Gal-3 and AKI in sepsis.
Here, we present a translational study of serum Gal-3 in sepsis and S-AKI. We aimed to explore the role of Gal-3 in the pathophysiology of S-AKI and its potential utility as a therapeutic target. We examined patients admitted to the ICU with sepsis and determined whether serum Gal-3 levels predicted subsequent development of AKI and ICU mortality. In a rat model of sepsis induced by cecal ligation and puncture (CLP), we evaluated the role of Gal-3 in the pathogenesis of S-AKI, as well as the potential utility of Gal-3 as a therapeutic target. We studied the effect of an oral Gal-3 inhibitor, modified citrus pectin, on S-AKI occurrence, mortality, and levels of serum Gal-3, IL-6, and creatinine, as well as the temporal relationship between the rise of serum Gal-3 and IL-6.
Discussion
In this translational study, we evaluated the role of Gal-3 in sepsis and S-AKI. We found that elevated Gal-3 levels at ICU admission predicted S-AKI and mortality in patients with sepsis, while inhibition of Gal-3 in a CLP rat model resulted in a statistically significant reduction in S-AKI and mortality. Together, these findings suggest that Gal-3 plays an important role in the pathophysiology of S-AKI and sepsis mortality.
In patients admitted to the ICU with sepsis, elevated serum Gal-3 levels at admission predicted ICU mortality. Our findings are consistent with other clinical research in which serum Gal-3 levels predicted 30-day all-cause mortality in sepsis [
26], as well as murine experiments demonstrating the important role of Gal-3 in sepsis pathogenesis and mortality [
27,
30]. Our findings suggest that serum Gal-3 may serve as a prognostic indicator in sepsis.
We also found that serum Gal-3 levels obtained at ICU admission were associated with subsequent AKI, as were two previously studied biomarkers of kidney injury, CysC and PCT [
50‐
52]. Further, Gal-3 levels predicted subsequent development of S-AKI after controlling for age and APACHE II score. This is the first report of such a finding in patients with sepsis. It is consistent with previous findings that preoperative serum Gal-3 predicts AKI after cardiac surgery [
27], and that Gal-3 at the time of ICU discharge is associated with severity of AKI [
28]. Our findings are also consistent with various murine experiments, which demonstrate that Gal-3 plays a role in the pathophysiology of AKI secondary to various insults [
28,
33‐
36]. In our patient study, 6 of the 8 observed deaths were in patients who had developed S-AKI, suggesting that the increased mortality seen in those with high Gal-3 levels may be mediated, at least in part, by impaired renal function [
53]. While there was an association between Gal-3 and AKI, the predictive ability of Gal-3 in the detection of AKI was lower than that of mortality. Notably, the patient study was limited by its observational nature, small sample size, and low mortality rate. The findings demonstrate an association of Gal-3 with both mortality and AKI, and warrant further evaluation of the role of Gal-3 in S-AKI and sepsis mortality.
In a CLP rat model, we found that administration of a Gal-3 inhibitor prior to CLP significantly reduced mortality and S-AKI rate in both P-MCP-treated groups. Inhibition of Gal-3 also resulted in a significant reduction in Gal-3 and IL-6 levels. The difference between IL-6 levels in the control and P-MCP-treated groups increased over time, reaching the greatest difference at 24 h post-CLP. Prior studies have also reported attenuation of IL-6 levels with Gal-3 knock out or Gal-3 inhibition [
28,
29,
35,
37].
In the control group, serum Gal-3 levels peaked earlier than serum IL-6: Gal-3 levels peaked at 2 h post-CLP and fell to near-baseline by 8 h, while IL-6 continued to rise throughout the entire 24 h post-procedure period. Comparatively, in the Gal-3 inhibitor groups, IL-6 levels decreased between 8 and 24 h post-procedure. Compared to controls, the decrease in IL-6 between 8 and 24 h was statistically significant in the 1200 mg P-MCP group only. Together, these findings suggest that serum Gal-3 release may precede the rise of IL-6 in the inflammatory cascade. Additionally, P-MCP-mediated Gal-3 inhibition may exert its effect in a dose dependent manner. At higher doses, Gal-3 inhibition may cause IL-6 levels to drop at an earlier time point.
Given the important role of IL-6 in the inflammatory cascade, these preliminary findings suggest that Gal-3 may serve as an upstream mediator of the “cytokine storm” in sepsis and S-AKI [
54]. Study limitations included small sample sizes, as well as limited follow-up time to monitor Cr rise. Additionally, given our aim to compare mortality among CLP groups, histological evaluation of renal tissue was not possible.
In humans, elevations in serum Gal-3 may persist for longer durations. In a study by Prud’homme et al
., 645 patients with AKI during their ICU stay demonstrated elevated serum Gal-3 levels at discharge [
28]. Further, Gal-3 levels at discharge were increasingly elevated with increased severity of AKI [
28]. Given these findings, Gal-3 may continue to play a role in the progression of AKI past the 2 to 8 h range detected in our rat model. Our findings warrant further investigation of the potential therapeutic utility of Gal-3 inhibition or removal in the prevention and treatment of S-AKI.
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